WO2016098857A1 - Préparation - Google Patents

Préparation Download PDF

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Publication number
WO2016098857A1
WO2016098857A1 PCT/JP2015/085382 JP2015085382W WO2016098857A1 WO 2016098857 A1 WO2016098857 A1 WO 2016098857A1 JP 2015085382 W JP2015085382 W JP 2015085382W WO 2016098857 A1 WO2016098857 A1 WO 2016098857A1
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WIPO (PCT)
Prior art keywords
particles
acid
active ingredient
preparation
fraction
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Application number
PCT/JP2015/085382
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English (en)
Japanese (ja)
Inventor
和志 伊藤
隆之 赤峰
紗織 利根
大地 川村
阿部　佳子
Original Assignee
積水化学工業株式会社
積水メディカル株式会社
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Application filed by 積水化学工業株式会社, 積水メディカル株式会社 filed Critical 積水化学工業株式会社
Priority to EP15870059.1A priority Critical patent/EP3235493A4/fr
Priority to US15/532,840 priority patent/US10729661B2/en
Priority to CN201580032834.3A priority patent/CN106604722A/zh
Priority to JP2016546533A priority patent/JP6091721B2/ja
Publication of WO2016098857A1 publication Critical patent/WO2016098857A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes

Definitions

  • the present invention relates to particles containing active ingredients, preparations containing the same, and the like.
  • Drugs that are absorbed from the skin, etc. are transferred to the systemic circulation, and are used externally that exhibit systemic effects (systemic action-type externally applied drugs), or drugs that are absorbed from the skin and the like are locally effective (local effects) External medicine).
  • cosmetics percutaneous absorption type cosmetics aiming to percutaneously absorb active ingredients are also used. In these preparations, how to effectively absorb the active ingredient into the body is a major technical problem.
  • Core core structure particles having a structure in which a core part containing an active ingredient is wrapped with a shell part containing a surfactant have been proposed as a preparation that allows the active ingredient to permeate the skin (Patent Documents 1 and 2).
  • a topical medicine such as a transdermally absorbable preparation
  • a topical medicine such as a transdermally absorbable preparation
  • a high medicinal effect is obtained shortly after the start of the administration, but the main drug in the preparation is depleted as a result of early absorption.
  • the medicinal effect is not sustained.
  • the blood concentration exceeds the level at which the drug effect is expressed and reaches the level at which the side effect occurs.
  • external medicines such as transdermally absorbable preparations have been required to have both absorbability into the body and sustainability.
  • storage stability of particles containing an active ingredient is also required.
  • the present inventors have found that the core-shell structure particles for external use that have been reported so far have a problem that they do not have sufficient durability and collapse during the preparation process. Specifically, for example, in the process of contact with a solvent for liquefaction or heat treatment for a coating process, the core-shell structure collapses, and the active ingredient in the core part precipitates or crystallizes. It has been found that problems such as elution occur. *
  • the present invention has both an absorbability into the body and sustainability, and also has an active ingredient that is excellent in shape retention (storage stability, durability such as solvent resistance and heat resistance) It is an object to provide particles.
  • Item 1 Particles comprising a first fraction containing an active ingredient and a second fraction containing a surfactant and having a number average particle diameter of 1 to 100 nm.
  • Item 2. The particle according to Item 1, wherein a part or all of the surface of the first fraction is covered with the second fraction.
  • Item 3. Item 3.
  • Item 1 or 2 wherein the number average particle size is 1 nm to 20 nm.
  • Item 4. The particles according to any one of Items 1 to 3, wherein the water content is 20% by weight or less.
  • Item 5. Item 5.
  • a preparation comprising the particle according to any one of Items 1 to 4.
  • Item 6. The preparation according to Item 5, wherein the water content is 20% by weight or less.
  • Item 7. The preparation according to Item 5 or 6, wherein the weight ratio of the active ingredient to the surfactant is 1:10 to 1:50.
  • Item 8. Item 8. An external preparation containing the preparation according to any one of Items 5 to 7.
  • Item 9. Item 8.
  • a cosmetic comprising the preparation according to any one of Items 5 to 7.
  • a method for producing particles comprising a first fraction containing an active ingredient and a second fraction containing a surfactant, wherein the aqueous phase contains an active ingredient and / or the W / O emulsion
  • grains including the process of heat-processing the dried material of an emulsion.
  • Item 11. The production method according to Item 10, wherein the number average particle diameter of the particles is 1 nm to 20 nm.
  • an active ingredient-containing particle that has both absorbability and sustainability and is excellent in shape retention (storage stability, durability such as solvent resistance and heat resistance). Can do. Since these particles have storage stability and durability, leakage of the active ingredient, and hence crystallization of the active ingredient, is further suppressed, and thereby higher absorbability can be exhibited.
  • absorbability to the body
  • skin permeability skin permeability
  • absorption through the skin for example, eye drops, nasal, intravaginal, rectal It includes the concept of “absorbability via internal (suppository)”.
  • the particle particles include at least two fractions: a first fraction containing an active ingredient and a second fraction containing a surfactant.
  • the first fraction and the second fraction may be combined with each other (preferably by intermolecular force) to form an aggregate.
  • the particles may be a part or all of the surface of the first fraction (for example, 30% or more, preferably 50% or more of the surface of the first fraction, more preferably 70% or more, more preferably 85% or more, still more preferably 95% or more, particularly preferably 99% or more) is preferably coated on the second fraction.
  • a core-shell structure in which the first fraction corresponds to a core portion and the second fraction includes a shell portion that includes the core portion can be mentioned.
  • the size of the particles is important for obtaining the effect of the present invention.
  • the number average particle diameter needs to be 1 nm to 100 nm.
  • the number average particle diameter is preferably 1 to 50 nm, more preferably 1 to 30 nm, still more preferably 1 to 20 nm, still more preferably 1 to 15 nm, and particularly preferably 2 nm to 10 nm. . *
  • the shape of the particles is not particularly limited. If the particle diameter is within the above range, it is possible to combine excellent absorbency of active ingredients, storage stability, and durability regardless of the shape.
  • Examples of the particle shape include a spherical shape, a rod shape, a cubic shape, a lens shape, and a sea urchin shape.
  • the number average particle diameter of the particles is calculated by calculating the number average diameter of the fraction showing a peak at 1 nm to 100 nm by a dynamic light scattering method when a solvent (for example, squalane) is dispersed. To do. *
  • the water content of the particles is preferably 20% by weight or less, more preferably 10% by weight or less, further preferably 5% by weight or less, still more preferably 1% by weight or less, and particularly preferably substantially contains water. do not do. That is, the particles of the present invention are different from the particles in the W / O emulsion.
  • the first fraction contains at least an active ingredient.
  • the active ingredient is not particularly limited as long as it is a physiologically active ingredient.
  • it is a component blended for the purpose of exerting its physiological activity.
  • those having physiological activity but not blended for the purpose of exerting the physiological activity are not included in the active ingredient from the viewpoint of blending amount, blending method and the like.
  • blended as an active ingredient for example to a pharmaceutical, cosmetics, etc. is mentioned. Since many active ingredients of pharmaceuticals and cosmetics are organic substances, the active ingredients may be organic substances.
  • any of those requiring a systemic action and those requiring a local action can be used.
  • the active ingredient included in the pharmaceutical are not particularly limited, for example, dementia therapeutics, antiepileptic drugs, antidepressants, antiparkinsonian drugs, antiallergic drugs, anticancer drugs, diabetes therapeutic drugs, antihypertensive drugs, Examples thereof include ED therapeutic agents, skin disease agents, local anesthetics, peptide drugs, and pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable salt is not particularly limited, and any of an acidic salt and a basic salt can be employed.
  • acid salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, and phosphate, acetate, propionate, tartrate, fumarate, maleate, apple Organic acid salts such as acid salts, citrate salts, methanesulfonate salts, benzenesulfonate salts, and paratoluenesulfonate salts.
  • the basic salt include alkali metal salts such as sodium and potassium, and alkaline earth metal salts such as calcium salt and magnesium salt.
  • salt of the active ingredient examples include memantine hydrochloride, donepezil hydrochloride, rivastigmine tartrate, galantamine hydrobromide, clomipramine hydrochloride, diphenhydramine hydrochloride, nalfurafine hydrochloride, metoprolol tartrate, fesoterodine fumarate, rudenafil Hydrochloride hydrate, Nalflaphine hydrochloride, Tandospirone citrate, Beraprost sodium, Lurasidone hydrochloride, Nefazodone hydrochloride, Benidipine hydrochloride, Doxazosin mesylate, Nicardipine hydrochloride, Formoterol fumarate, Lomeridine hydrochloride, Amlodipine besil Examples include acid salts.
  • the active ingredient blended in the cosmetic is not particularly limited as long as skin permeation is required.
  • vitamin ingredients such as vitamin C and vitamin E
  • moisturizing ingredients such as hyaluronic acid, ceramide and collagen
  • tranexamic acid examples include whitening components such as arbutin, hair growth components such as minoxidil, cosmetic components such as FGF (fibroblast growth factor) and EGF (epidermal growth factor), and salts and derivatives thereof.
  • a hydrophilic one is preferable.
  • the active ingredient is not particularly limited when it is a hydrophilic drug, but typically has the following characteristics:
  • the molecular weight is 10,000 or less, and the octanol water partition coefficient is ⁇ 6 to 6.
  • the molecular weight is preferably 5000 or less, more preferably 2000 or less, and still more preferably 1000 or less. Although the minimum of molecular weight is not specifically limited, Usually, it is 50 or more.
  • the octanol water partition coefficient is preferably -3 to 5, more preferably -1 to 4.
  • the octanol water partition coefficient is calculated by the following formula from the drug concentration of each phase after adding the drug into a flask containing octanol and an aqueous buffer solution of pH 7 and then shaking. . *
  • Octanol water partition coefficient Log 10 (concentration in octanol phase / concentration in water phase)
  • the amount of the active ingredient contained in the particles depends on the type of the active ingredient.
  • the raw material charge weight is 0.1 to 30% by weight (based on the total weight of all the raw materials contained in the particles). be able to. *
  • the first fraction may contain two or more active ingredients as active ingredients as necessary. *
  • the first fraction may further contain at least one other component in addition to the active component.
  • at least one other component for example, a stabilizer, an absorption promoter, a stimulus reducing agent, a preservative, etc. are mentioned. *
  • the stabilizer has a function of stabilizing the particle structure, prevents unintended early collapse of the particle structure, and ensures a sustained release effect of the active ingredient.
  • the stabilizer is not particularly limited, and specific examples include polysaccharides, proteins, and hydrophilic polymer materials.
  • a stabilizer may contain 1 type, or 2 or more types.
  • the content of the stabilizer in the first fraction can be appropriately set depending on the type of the stabilizer. For example, the weight ratio of the active ingredient and the stabilizer is 1: 0.1 to 1:10. It can also be blended. .
  • the absorption promoter is not particularly limited, and specifically includes higher alcohols, N-acyl sarcosine and salts thereof, higher monocarboxylic acids, higher monocarboxylic acid esters, aromatic monoterpene fatty acid esters, 2 to 10 carbon atoms. And divalent carboxylic acids and salts thereof, polyoxyethylene alkyl ether phosphates and salts thereof, lactic acid, lactic acid esters, and citric acid.
  • the absorption promoter may contain 1 type (s) or 2 or more types.
  • the content of the absorption enhancer in the first fraction can be appropriately set depending on the type, but for example, the weight ratio of the active ingredient to the absorption enhancer is 1: 0.01 to 1:50. It can also be blended.
  • the irritation reducing agent is not particularly limited, but specifically, hydroquinone glycoside, pantethine, tranexamic acid, lecithin, titanium oxide, aluminum hydroxide, sodium nitrite, sodium hydrogen nitrite, soybean lecithin, methionine, glycyrrhetin Examples include acids, BHT, BHA, vitamin E and derivatives thereof, vitamin C and derivatives thereof, benzotriazole, propyl gallate, and mercaptobenzimidazole.
  • the irritation reducing agent may contain one kind or two or more kinds.
  • the content ratio of the irritation reducing agent in the first fraction can be set as appropriate depending on the type of the agent, but for example, it can be blended so as to be 0.1 wt% to 50 wt%. *
  • Preservatives are not particularly limited, and specific examples include methyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol and thymol.
  • the content of the preservative in the first fraction can be set as appropriate depending on the type of the preservative, but it can also be blended so as to be, for example, 0.01 wt% to 10 wt%.
  • preservative may contain 1 type (s) or 2 or more types. *
  • the second fraction contains at least a surfactant.
  • HLB values 10 or less, preferably 5 or less, more preferably 3 or less.
  • an HLB abbreviation of Hydrophile Lipophile Balance
  • HLB Hydrophile Lipophile Balance
  • HLB value 20 ⁇ ⁇ (molecular weight of hydrophilic portion) / (total molecular weight) ⁇
  • the weighted average value of the HLB value is calculated as follows.
  • surfactant raw materials with HLB values A, B, and C
  • formula for calculating the weighted average value when the charged weight at the time of synthesis of each particle is x, y, z is (XA + yB + zC) ⁇ (x + y + z)
  • the surfactant is preferably one having a melting point of 50 ° C. or lower, more preferably 40 ° C. or lower in terms of absorbability.
  • the surfactant is not particularly limited and can be appropriately selected depending on the application. For example, it can be widely selected from those that can be used as pharmaceuticals and cosmetics. A plurality of types of surfactants may be used in combination. *
  • the surfactant may be any of a nonionic surfactant, an anionic surfactant, a cationic surfactant and an amphoteric surfactant.
  • Nonionic surfactants include, but are not limited to, fatty acid esters, fatty alcohol ethoxylates, polyoxyethylene alkyl phenyl ethers, alkyl glycosides and fatty acid alkanolamides, and polyoxyethylene castor oil and hydrogenated castor oil. . *
  • the fatty acid ester is not particularly limited, but a sugar fatty acid ester is preferable. Specific examples include esters of sucrose with fatty acids such as erucic acid, oleic acid, lauric acid, stearic acid and behenic acid. *
  • fatty acid esters are not particularly limited, and examples include esters of fatty acids with at least one of glycerin, polyglycerin, polyoxyethylene glycerin, sorbitan, and polyoxyethylene sorbit. *
  • anionic surfactant examples include alkyl sulfate ester salts, polyoxyethylene alkyl ether sulfate ester salts, alkylbenzene sulfonate salts, fatty acid salts, and phosphate ester salts.
  • cationic surfactant examples include alkyl trimethyl ammonium salts, dialkyl dimethyl ammonium salts, alkyl dimethyl benzyl ammonium salts, and amine salts. *
  • amphoteric surfactants include alkylamino fatty acid salts, alkylbetaines, and alkylamine oxides. *
  • sucrose fatty acid ester sucrose fatty acid ester, glycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbite fatty acid ester, polyoxyethylene castor oil and hydrogenated castor oil are particularly preferably used.
  • the surfactant is not particularly limited, but may have a hydrocarbon chain (an alkyl chain, an alkenyl chain, an alkynyl chain, etc.).
  • the hydrocarbon chain length is not particularly limited, but the number of carbon atoms on the main chain can be widely selected from 8 to 30, and is preferably 10 to 24. .
  • the total weight of the active ingredient and the hydrocarbon chain contained in the surfactant When only a surfactant having a hydrocarbon chain is used, or when a surfactant having a hydrocarbon chain is used in combination with another surfactant, the total weight of the active ingredient and the hydrocarbon chain contained in the surfactant When the ratio is from 1: 1 to 1:70, the particles of the present invention have excellent absorbability.
  • the same weight ratio is preferably 1: 2 to 1:70 or 1: 2 to 1:50, more preferably 1: 3 to 1:30, and 1: 5 to 1:20. Is even more preferred.
  • the second fraction may further contain at least one other component in addition to the surfactant.
  • at least one other component for example, an irritation
  • the irritation reducing agent is not particularly limited, but specifically, hydroquinone glycoside, pantethine, tranexamic acid, lecithin, titanium oxide, aluminum hydroxide, sodium nitrite, sodium hydrogen nitrite, soybean lecithin, methionine, glycyrrhetin Examples include acids, BHT, BHA, vitamin E and derivatives thereof, vitamin C and derivatives thereof, benzotriazole, propyl gallate, and mercaptobenzimidazole.
  • the irritation reducing agent may contain one kind or two or more kinds.
  • the content ratio of the irritation reducing agent in the second fraction can be set as appropriate depending on the type, but it can also be blended so as to be, for example, 0.1 wt% to 50 wt%. *
  • the analgesic is not particularly limited, and specific examples include local anesthetics such as procaine, tetracaine, lidocaine, dibucaine and prilocaine, and salts thereof.
  • An analgesic may contain 1 type (s) or 2 or more types.
  • the content ratio of the analgesic agent in the second fraction can be appropriately set depending on the type of the analgesic agent, but it can also be blended to be, for example, 0.1 wt% to 30 wt%. *
  • the absorption promoter is not particularly limited, and specifically includes higher alcohols, N-acyl sarcosine and salts thereof, higher monocarboxylic acids, higher monocarboxylic acid esters, aromatic monoterpene fatty acid esters, 2 to 10 carbon atoms. And divalent carboxylic acids and salts thereof, polyoxyethylene alkyl ether phosphates and salts thereof, lactic acid, lactic acid esters, and citric acid.
  • the absorption promoter may contain 1 type (s) or 2 or more types.
  • the content ratio of the absorption accelerator in the second fraction can be appropriately set depending on the type, but it can also be blended to be, for example, 0.1 wt% to 30 wt%. *
  • the stabilizer has a function of stabilizing the core-shell structure, prevents unintended early collapse of the core-shell structure, and ensures a sustained release effect of the active ingredient.
  • the stabilizer is not particularly limited, and specifically, fatty acids and salts thereof, parahydroxybenzoates such as methylparaben and propylparaben, alcohols such as chlorobutanol, pendyl alcohol, and phenylethyl alcohol, thimerosal , Acetic anhydride, sorbic acid, sodium hydrogen sulfite, L-ascorbic acid, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate, tocopherol acetate, dl- ⁇ -tocopherol, protein and polysaccharides.
  • a stabilizer may contain 1 type, or 2 or more types.
  • the content of the stabilizer in the second fraction can be appropriately set depending on the type of the stabilizer. For example, the weight ratio of the sucrose fatty acid ester to the stabilizer is 1: 0.01 to 1:50. It can also be blended. *
  • Preservatives are not particularly limited, and specific examples include methyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol and thymol.
  • preservative may contain 1 type (s) or 2 or more types.
  • the content of the preservative in the second fraction can be set as appropriate depending on the type of the preservative, but for example, it can be blended so as to be 0.01 wt% to 10 wt%. *
  • formulation of the present invention contains at least the particles.
  • the content ratio of the particles in the preparation is not particularly limited, but in the case of a patch, ointment, cream, or gel, it is preferably 10% by weight to 70% by weight, more preferably 20% by weight to 50% by weight. It is as follows. *
  • the weight ratio of the active ingredient to the surfactant in the preparation can be appropriately set within the range where the effects of the present invention are exerted, for example, 1: 3 to 1: 100. At this time, the preparation of the present invention has excellent absorbability. In this respect, the weight ratio is preferably 1: 5 to 1: 100, more preferably 1:10 to 1:50 or 1:15 to 1:50. *
  • the preparation of the present invention is a preparation intended for percutaneous absorption or transmucosal absorption, such as external preparations (for example, external preparations for skin, eye drops, nasal drops, suppositories, oral preparations, etc.) or cosmetics, depending on the type of active ingredient It can be used for a wide range of applications.
  • external preparations for example, external preparations for skin, eye drops, nasal drops, suppositories, oral preparations, etc.
  • cosmetics depending on the type of active ingredient It can be used for a wide range of applications.
  • the preparation of the present invention is not particularly limited, but is usually sustained for 1 day to 1 week, and in a preferred embodiment, it is used so as to be applied once a day to 1 week.
  • the target disease varies depending on the type of active ingredient.
  • the preparation of the present invention is not particularly limited, and is a patch (plaster, plaster, etc., tape (reservoir type, matrix type, etc.), cataplasm, patch, microneedle, etc.), ointment, external liquid (liniment). Agents, lotions, etc.), sprays (external aerosols, pump sprays, etc.), creams, gels, eye drops, eye ointments, nasal drops, suppositories, rectal semisolids, enemas, etc. Can be used.
  • the preparation of the present invention preferably has a water content of 20% by weight or less, and more preferably contains substantially no water. As a result, it is possible to further improve the shape retention of the particles, and in combination with the shape retention inherent to the particles, leakage of the active ingredient from the particles, and thus crystallization of the active ingredient can be further suppressed. As a result, it is possible to exhibit higher absorbency.
  • the preparation of the present invention is an agent whose water content is adjusted to 20% by weight or less (more preferably an agent that does not substantially contain water), such as a plaster agent, patch agent, ointment agent, gel agent and the like. It is preferable to be used as *
  • Formulations 2.1 groups agent phase present invention further contain a phase containing a base (base phase), the base phase may be those containing the particles. At this time, the particles are dispersed or dissolved in the base phase.
  • the base is not particularly limited, and can be widely selected from drugs that can be used as pharmaceuticals (especially external medicines) and cosmetics. *
  • the base can be appropriately selected from those suitable for dispersing or dissolving the particles according to the purpose of use, and is not particularly limited. *
  • the base is not particularly limited, and examples thereof include an oily base and an aqueous base.
  • oily bases include vegetable oils, animal oils, neutral lipids, synthetic fats and oils, sterol derivatives, waxes, hydrocarbons, monoalcohol carboxylic acid esters, oxyacid esters, polyhydric alcohol fatty acid esters, silicones, Examples include higher alcohols, higher fatty acids, and fluorine-based oils.
  • aqueous base include water and (polyhydric) alcohol. Is mentioned.
  • the vegetable oil is not particularly limited, and examples thereof include soybean oil, sesame oil, olive oil, palm oil, balm oil, rice bran oil, cottonseed oil, sunflower oil, rice bran oil, cacao butter, corn oil, bean flower oil, castor oil and rapeseed oil. Can be mentioned. *
  • Animal oil is not particularly limited, and examples thereof include mink oil, turtle oil, fish oil, cow oil, horse oil, pig oil, and salmon squalane. *
  • the neutral lipid is not particularly limited, and examples thereof include triolein, trilinolein, trimyristin, tristearin, and triarachidonin. *
  • Synthetic fats and oils are not particularly limited, and examples thereof include phospholipids and azones. *
  • the sterol derivative is not particularly limited, and examples thereof include dihydrocholesterol, lanosterol, dihydrolanosterol, phytosterol, cholic acid, and cholesteryl linoleate. *
  • waxes examples include candelilla wax, carnauba wax, rice wax, beeswax, beeswax, montan wax, ozokerite, ceresin, paraffin wax, microcrystalline wax, petrolatum, Fischer-Tropsch wax, polyethylene wax, and ethylene / propylene copolymer. Can be mentioned. *
  • hydrocarbons examples include liquid paraffin (mineral oil), heavy liquid isoparaffin, light liquid isoparaffin, ⁇ -olefin oligomer, polyisobutene, hydrogenated polyisobutene, polybutene, squalane, olive-derived squalane, squalene, petrolatum and solid paraffin. It is done. *
  • Monoalcohol carboxylates include octyldodecyl myristate, hexyl decyl myristate, octyl dodecyl isostearate, cetyl palmitate, octyl dodecyl palmitate, cetyl octoate, hexyldecyl octoate, isotridecyl isononanoate, isononanoyl isononanoate, Octyl isononanoate, isotridecyl isononanoate, isodecyl neopentanoate, isotridecyl neopentanoate, isostearyl neopentanoate, octyldodecyl neodecanoate, oleyl oleate, octyl dodecyl oleate, octyldodecy
  • oxyesters examples include cetyl lactate, diisostearyl malate, and hydrogenated castor oil monoisostearate. *
  • Polyhydric alcohol fatty acid esters include glyceryl trioctanoate, glyceryl trioleate, glyceryl triisostearate, glyceryl diisostearate, glyceryl tri (caprylic acid / capric acid), tri (caprylic acid / capric acid / myristic acid / stearic acid) ) Glyceryl, hydrogenated rosin triglyceride (hydrogenated ester gum), rosin triglyceride (ester gum), glyceryl behenate, trimethylolpropane trioctanoate, trimethylolpropane triisostearate, neopentylglycol dioctanoate, neopentyl glycol dicaprate Pentyl glycol, 2-butyl-2-ethyl-1,3-propanediol dioctanoate, propylene glycol dioleate, pentaerythrate
  • Silicones include dimethicone (dimethylpolysiloxane), highly polymerized dimethicone (highly polymerized dimethylpolysiloxane), cyclomethicone (cyclic dimethylsiloxane, decamethylcyclopentasiloxane), phenyltrimethicone, diphenyldimethicone, phenyldimethicone, stearoxypropyl.
  • Polyether modification such as dimethylamine, (aminoethylaminopropylmethicone / dimethicone) copolymer, dimethiconol, dimethiconol crosspolymer, silicone resin, silicone rubber, amino-modified silicone such as aminopropyldimethicone or amodimethicone, cation-modified silicone, dimethicone copolyol Silicone, polyglycerin modified silicone, sugar modified silicone, carboxylic acid modified silicone, phosphoric acid modified silicone , Sulfuric acid modified silicone, alkyl modified silicone, fatty acid modified silicone, alkyl ether modified silicone, amino acid modified silicone, peptide modified silicone, fluorine modified silicone, cation modified or polyether modified silicone, amino modified or polyether modified silicone, alkyl modified or poly Examples thereof include ether-modified silicones and polysiloxane / oxyalkylene copolymers.
  • Examples of higher alcohols include cetanol, myristyl alcohol, oleyl alcohol, lauryl alcohol, cetostearyl alcohol, stearyl alcohol, aralkyl alcohol, behenyl alcohol, jojoba alcohol, chimyl alcohol, ceralkyl alcohol, batyl alcohol, hexyldecanol, isostearyl alcohol, Examples include 2-octyldodecanol and dimer diol. *
  • Higher fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, behenic acid, undecylenic acid, 12-hydroxystearic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, erucic acid, docosahexaenoic acid Eicosapentaenoic acid, isohexadecanoic acid, anteisohenicosanoic acid, long-chain branched fatty acid, dimer acid and hydrogenated dimer acid. *
  • Fluorinated oils include perfluorodecane, perfluorooctane and perfluoropolyether. *
  • Polyhydric alcohol includes ethanol, isopropanol, glycerin, propylene glycol, 1,3-butylene glycol, polyethylene glycol and the like. *
  • bases are not particularly limited, but include patches (plasters, plasters and other tapes (reservoir type, matrix type, etc.), poultices, patches, microneedles, etc.), ointments, external use Liquids (liniments, lotions, etc.), sprays (external aerosols, pump sprays, etc.), creams, gels, eye drops, eye ointments, nasal drops, suppositories, rectal semisolids, enemas Examples include bases used in preparations.
  • the preparation of the present invention may contain other additive components depending on the dosage form, purpose of use, and the like.
  • Additive components are not particularly limited, but include excipients, colorants, lubricants, binders, emulsifiers, thickeners, wetting agents, stabilizers, preservatives, solvents, solubilizers, suspending agents, Buffering agents, pH adjusting agents, gelling agents, pressure-sensitive adhesives, antioxidants, absorption accelerators, stimulus relaxation agents, preservatives, chelating agents, and dispersing agents can be used.
  • excipients include excipients, colorants, lubricants, binders, emulsifiers, thickeners, wetting agents, stabilizers, preservatives, solvents, solubilizers, suspending agents, Buffering agents, pH adjusting agents, gelling agents, pressure-sensitive adhesives, antioxidants, absorption accelerators, stimulus relaxation agents, preservatives, chelating agents, and dispersing agents can be used.
  • the preparation of the present invention when the base phase is not included, the particles are included, or when the base phase is included, the base phase in which the particles are included (hereinafter collectively referred to as “particles”). It may be referred to as “containing basic component”), and may be dispersed in other components.
  • the preparation of the present invention is provided by mixing and dispersing or emulsifying particles or particle-containing basic components in a component in which particles or particle-containing basic components are not completely dissolved. It can be appropriately selected depending on the dosage form, and is not particularly limited.
  • a patch a plaster, a plaster, a tape (reservoir, matrix, etc.), a cataplasm, a patch, a microneedle, etc.), an ointment, etc.
  • particles or particle-containing basic components can be mixed and dispersed or emulsified in the base used in each dosage form.
  • the particles of the present invention are not particularly limited, but can be produced, for example, by a method including a step of drying a W / O emulsion containing an active ingredient in an aqueous phase.
  • the W / O emulsion is not particularly limited as long as it is a so-called water-in-oil emulsion, specifically, an emulsion in which droplets of an aqueous solvent are dispersed in an oily solvent.
  • the W / O emulsion containing the active ingredient in the aqueous phase is, for example, an aqueous solvent containing the active ingredient (eg, water, buffered aqueous solution, etc.) and an oily solvent containing a surfactant (eg, cyclohexane, hexane, toluene, etc.) Can be obtained by mixing.
  • the aqueous solvent containing the active ingredient may contain additive components such as a stabilizer, an absorption accelerator, and an irritation reducing agent, if necessary, in addition to the active ingredient.
  • the oily solvent containing the surfactant may contain additional components such as an irritation reducing agent, an analgesic agent, an absorption accelerator, and a stabilizer, as necessary, in addition to the active ingredient.
  • the mixing method is not particularly limited as long as it is a method capable of forming a W / O emulsion, and examples thereof include stirring with a homogenizer or the like.
  • the conditions at the time of stirring the homogenizer are, for example, about 5000 to 50000 rpm, more preferably about 10,000 to 30000 rpm. *
  • the weight ratio of the active ingredient to the surfactant in the W / O emulsion can finally give the particles of the present invention having a number average particle diameter of 1 to 100 nm.
  • it is 1: 3 to 1: 100, preferably 1: 5 to 1:70, more preferably 1:10 to 1:50.
  • the method for drying the W / O emulsion containing the active ingredient in the aqueous phase is not particularly limited as long as it is a method capable of removing the solvent (aqueous solvent and oily solvent) in the emulsion. For example, freeze drying, drying under reduced pressure, etc. However, lyophilization is preferable. *
  • a W / O emulsion containing an active ingredient in an aqueous phase or a dried product of the W / O emulsion (preferably the W / O emulsion). It is preferable that a step of heat-treating the dried product is further included.
  • the heat treatment temperature is, for example, 30 to 60 ° C., preferably 35 to 50 ° C., more preferably 35 to 45 ° C.
  • the heat treatment time is appropriately adjusted according to the heat treatment temperature, and is, for example, 1 to 30 days, preferably 2 to 15 days, more preferably 3 to 7 days.
  • this W / O emulsion is heat-processed, the particle
  • Another method for reducing the number average particle size of the obtained particles is a W / O emulsion containing an active ingredient in the aqueous phase or a dried product of the W / O emulsion (preferably the W / O emulsion).
  • Examples thereof include a method of dispersing a dried product) in a solvent or the like as necessary, followed by filtering with a filter or the like, or a method of performing centrifugal separation.
  • the filter pore diameter in the case of filter filtration is, for example, 1 ⁇ m or less, preferably 0.2 ⁇ m or less, more preferably 0.1 ⁇ m or less.
  • the particles of the present invention may be used as they are, but may be used by dispersing in the above-mentioned base or the like.
  • a preparation can be produced by a solution coating method.
  • a solvent such as hexane, toluene, or ethyl acetate is used so that additional components such as an absorption accelerator, a thickener, and a gelling agent are added at a predetermined ratio as desired. And stir to prepare a homogeneous solution.
  • the solid content concentration in the solution is preferably 10 to 80% by weight, more preferably 20 to 60% by weight.
  • a release liner silicone-treated polyester film, etc.
  • a coating machine such as a knife coater, comma coater, or reverse coater, and dried.
  • a preparation can be obtained by completing a drug-containing layer and laminating a support on the layer.
  • a release liner may be laminated on the surface of the layer.
  • the particles of the present invention may be added and mixed with additives such as a base, an absorption accelerator, a stabilizer, a thickener, and a gelling agent as necessary, depending on the use.
  • additives such as a base, an absorption accelerator, a stabilizer, a thickener, and a gelling agent as necessary, depending on the use.
  • Natural fabric members such as gauze or absorbent cotton, synthetic fiber fabric members such as polyester or polyethylene, or a combination of these appropriately processed into a woven fabric or nonwoven fabric, or laminated or impregnated on a permeable membrane, etc. It can also be used by covering it with an adhesive cover material or the like.
  • the thus obtained preparation is appropriately cut into an oval shape, a circular shape, a square shape, a rectangular shape or the like according to the intended use. Moreover, you may provide an adhesive phase etc. in the periphery as needed.
  • the number average particle diameter calculated by a dynamic light scattering method was 12 nm.
  • the number average particle size calculated by a dynamic light scattering method (Spectres Inc., Zetasizer-Nano S) was 39 nm.
  • the precipitate obtained by centrifugation (12000 rpm) was added to 11.4 g of isopropyl myristate and dispersed by stirring with a stirrer to produce a comparative external preparation.
  • the number average particle diameter calculated by a dynamic light scattering method (Spectres Inc., Zetasizer-Nano S) was 830 nm.
  • Test Example 1 Hairless Rat Skin Permeability Test Hairless rat skin (extracted from Japan SLC, HWY / Slc, 8 weeks old) was set in a drug skin permeation test cell (FIG. 1). 2 ml of the various external preparations produced in Examples 1 to 3 and Comparative Example 1 or the external preparation produced in Comparative Example 2 is applied to the upper part of this apparatus, and NaH 2 PO 4 is added to distilled water in the lower receptor layer.
  • Figure 2 shows the results. In Comparative Examples 1 and 2, the drug permeation amount increased rapidly, and permeation amount saturation occurred in a short time. *
  • Test example 2 Shape stability test The stability of the manufactured evaluation sample was confirmed using the shape of the preparation using an optical microscope (manufactured by Nikon Corporation, Eclipse ME600 model number) (200 times magnification) as an index. What passed 2 days on the room temperature condition of 25 degreeC was compared with the shape of an initial state, and the following evaluation items were used for the parameter
  • Table 1 shows the results of examining the stability of various evaluation samples.
  • Comparative Example 1 the change in shape was remarkably observed, whereas in the external preparation of the example, the change was slight. From these results, it was confirmed that the external preparation of the example was shape-stable.
  • Example 4 0.1 g of donepezil hydrochloride (manufactured by Nacalai Tesque) was dissolved in 40 g of pure water, and 1.5 g of sucrose erucic acid ester (manufactured by Mitsubishi Chemical Foods, ER-290; HLB value 2) was added to 80 g of cyclohexane. The solution dissolved in was added and stirred with a homogenizer (25,000 rpm). Thereafter, the particles were freeze-dried for 2 days and then allowed to stand at 40 ° C. for 5 days to prepare particles.
  • sucrose erucic acid ester manufactured by Mitsubishi Chemical Foods, ER-290; HLB value 2
  • Example 5 1.5 g of the particles obtained in Example 4 were added to 1.5 g of Plastic Base (manufactured by Taisho Pharmaceutical Co., Japan Pharmacopoeia), mixed and dispersed to produce an external preparation.
  • Plastic Base manufactured by Taisho Pharmaceutical Co., Japan Pharmacopoeia
  • Comparative Example 4 An external preparation was produced in the same manner as in Example 5 except that the particles obtained in Comparative Example 3 were used.
  • Comparative Example 7 0.094 g of donepezil hydrochloride was added to 1.5 g of plastic base, mixed and dispersed to prepare an external preparation.
  • Test Example 3 Durability Test The particles of Examples 4 and 6 to 11 and Comparative Examples 3 and 5 to 6 were dispersed in ethyl acetate (manufactured by Wako Pure Chemical Industries, Ltd.) at a concentration of 30% by weight, and the solvent was removed at 60 ° C. Then, it was dispersed in olive squalane, and the changes from the state in which the particles of Examples 4 and 6 to 11 and Comparative Examples 3 and 5 to 6 were dispersed in olive squalane were visually observed. The following evaluation items were used as indicators. (Shape evaluation item) ⁇ : No change ⁇ : Partial change ⁇ : Change
  • Table 2 shows the results of studies on the durability of various evaluation samples.
  • the state change (estimated to be due to particle collapse) was remarkably observed, whereas the change in the example particles was slight.
  • Test Example 4 Hairless Rat Skin Permeability Test Hairless rat skin (extracted from Japan SLC, HWY / Slc, 8 weeks old) was set in a drug skin permeation test cell (FIG. 1). 0.5 g (about 3 cm 2 ) of various external preparations produced in Example 5 and Comparative Examples 4 and 7 was applied to the upper part of this apparatus, and 5 ⁇ 10 5 NaH 2 PO 4 was added to distilled water in the lower receptor layer.
  • HPLC high performance liquid chromatography
  • Figure 3 shows the results. In the external preparation of Example 5, it was found that the amount of drug permeation was continuously large compared to the external preparation of Comparative Example 7, which was equal to or higher than that of Comparative Example 4. *
  • the particles of the Examples have a large amount of skin permeation, and are stable and highly durable.

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Abstract

L'invention concerne des particules comprenant chacune une première section contenant un ingrédient actif et une deuxième section contenant un tensioactif, ces particules ayant un diamètre moyen de particules en nombre compris entre 1 et 100 nm.
PCT/JP2015/085382 2014-12-19 2015-12-17 Préparation WO2016098857A1 (fr)

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US15/532,840 US10729661B2 (en) 2014-12-19 2015-12-17 Preparation
CN201580032834.3A CN106604722A (zh) 2014-12-19 2015-12-17 制剂
JP2016546533A JP6091721B2 (ja) 2014-12-19 2015-12-17 製剤

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WO2017002865A1 (fr) * 2015-06-29 2017-01-05 積水化学工業株式会社 Structure noyau/enveloppe et agent topique
WO2017119506A1 (fr) * 2016-01-06 2017-07-13 積水化学工業株式会社 Particules et préparation pharmaceutique
JP2018070535A (ja) * 2016-11-01 2018-05-10 積水化学工業株式会社 有効成分含有粒子、製剤、外用薬、化粧品及び注射剤
WO2019068846A1 (fr) * 2017-10-06 2019-04-11 Chanel Parfums Beaute Composition non aqueuse à usage externe sur la peau et son procédé de production
WO2019068847A1 (fr) * 2017-10-06 2019-04-11 Chanel Parfums Beaute Procédé de production de composition non-aqueuse pour un usage externe sur la peau

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WO2017002865A1 (fr) * 2015-06-29 2017-01-05 積水化学工業株式会社 Structure noyau/enveloppe et agent topique
JPWO2017002865A1 (ja) * 2015-06-29 2017-06-29 積水化学工業株式会社 コアシェル構造体及び外用剤
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WO2017119506A1 (fr) * 2016-01-06 2017-07-13 積水化学工業株式会社 Particules et préparation pharmaceutique
JP2018070535A (ja) * 2016-11-01 2018-05-10 積水化学工業株式会社 有効成分含有粒子、製剤、外用薬、化粧品及び注射剤
WO2019068846A1 (fr) * 2017-10-06 2019-04-11 Chanel Parfums Beaute Composition non aqueuse à usage externe sur la peau et son procédé de production
WO2019068847A1 (fr) * 2017-10-06 2019-04-11 Chanel Parfums Beaute Procédé de production de composition non-aqueuse pour un usage externe sur la peau
US11298298B2 (en) 2017-10-06 2022-04-12 Chanel Parfums Beaute Method for producing nonaqueous composition for external use on skin

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US10729661B2 (en) 2020-08-04
JP6091721B2 (ja) 2017-03-08
EP3235493A4 (fr) 2018-05-30
US20170354614A1 (en) 2017-12-14
CN106604722A (zh) 2017-04-26
JP2017048252A (ja) 2017-03-09
JPWO2016098857A1 (ja) 2017-04-27

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